Vital organ failure is one of the most critical problems facing the health care field today. Organ transplantation, as currently practiced, has become a major lifesaving therapy for patients afflicted with diseases that destroy vital organs including the heart, liver, lungs, kidney and intestine. However, the shortage of organs needed for transplantation has become critical and continues to worsen. For example, in the United States, the number of patients awaiting an organ for transplant has risen above 75,000. Despite advances in living donor organ transplantation, a severe shortage of donor organs available to these patients remains as the crux of the problem. Likewise, every major field of reconstructive surgery reaches the same barrier of tissue shortage. Orthopedic surgery, vascular surgery, cardiac surgery, general surgery, neurosurgery, and the others all share this fundamental problem. Therefore, countless patients suffer as a result. Mechanical devices provide one approach to addressing the organ and tissue shortage. Xenografts provide another approach. However, due to the intrinsic limitations of these technologies, these approaches are only partial solutions to the problem.
Over the last several years, the new field of tissue engineering has arisen to meet this need. The field brings the expertise of physicians, life scientists and engineers together to solve problems of generating new tissues for transplantation and surgical reconstruction. Tissue engineering can be a complete and permanent solution to the problem of organ loss or failure, but the primary challenge for tissue engineering vital organs is the requirement for a vascular supply for nutrient and metabolite transfer. The initial approaches to this problem were described in the 1980's. Yannas, et al., Science 221, 1052 (1981) and Burke, et al., Ann Surg 194, 413 (1981) relate to methods to generate new tissues in vivo by implanting non-living materials such as modified collagens which are seeded with cells to promote guided regeneration of tissue such as skin. Langer, et al. Science 260, 920 (1993) and Vacanti, et al., Materials Research Society 252, 367 (1992) involve synthetic fibrous matrices to which tissue specific cells were added in vitro. The matrices are highly porous and allow mass transfer to the cells in vitro and after implantation in vivo. After implantation, new blood vessels grow into the devices to generate a new vascularized tissue. However, the relatively long time course for angiogenesis limits the size of the newly formed tissue.
The field of Tissue Engineering is undergoing explosive growth. See, for example, Vacanti, et al., Lancet 354, 32 (1999); Langer, et al., Science 260, 920 (1993); Rennie, J. Scientific American 280, 37 (1999); and Lysaght, et al., Tissue Eng 4, 231 (1998). Virtually every tissue and organ of the body has been studied; many tissue-engineering technologies are becoming available. See Lysaght, et al. Tissue Eng 4, 231 (1998); Bell, et al., Science 221, 1052 (1981); Burke, et al., Ann Surg 194, 413 (1981); Compton, et al., Laboratory Investigation 60, 600 (1989); Parenteau, et al., Journal of Cellular Biochemistry 45, 24 (1991); Parenteau, et al., Biotechnology and Bioengineering 52, 3 (1996); Purdue, et al., J. Burn Care Rehab 18, 52 (1997); Hansbrough and Franco, Clinical Plastic Surg 25, 407 (1998); Vacanti, et al., Materials Research Society 252, 367 (1992).
Over time, several techniques to engineer new living tissue have been studied. Technologies include the use of growth factors to stimulate wound repair and regeneration, techniques of guided tissue regeneration using non-living matrices to guide new tissue development, cell transplantation, and cell transplantation on matrices. More recently, new understanding in stem cell biology has led to studies of populations of primordial cells, stem cells, or embryonic stem cells to use in tissue engineering approaches.
In parallel to these advances, the rapidly emerging field of MicroElectroMechanical Systems (MEMS) has penetrated a wide array of applications, in areas as diverse as automotives, inertial guidance and navigation, microoptics, chemical and biological sensing, and, most recently, biomedical engineering, McWhorter, et al. “Micromachining and Trends for the Twenty-First Century”, in Handbook of Microlithography, Micromachining and Microfabrication, ed. P. Rai-Choudhury, (Bellingham, Wash.: SPIE Press, 1997). Microfabrication technology has been used in important studies in cell and developmental biology to understand complex biologic signaling events occurring at the cell membrane-surface interface, as described, for example, by Kane, et al., Biomaterials 20, 2363 (1999). It has also been used in tissue engineering to guide cell behavior and the formation of small units of tissue, as described by Griffith, et al., Annals of Biomed Eng., 26 (1998).
Microfabrication methods for MEMS represent an extension of semiconductor wafer process technology originally developed for the integrated circuit (IC) industry. Control of features down to the submicron level is routinely achieved in IC processing of electrical circuit elements; MEMS technology translates this level of control into mechanical structures at length scales stretching from less than 1 micron (μm) to greater than 1 centimeter (cm). Standard bulk micromachining enables patterns of arbitrary geometry to be imprinted into wafers using a series of subtractive etching methods. Three-dimensional structures can be realized by superposition of these process steps using precise alignment techniques. Several groups (Griffith, et al., Annals of Biomed. Eng., 26 (1998); Folch, et al., Biotechnology Progress, 14, 388 (1998)) have used these highly precise silicon arrays to control cell behavior and study gene expression and cell surface interactions. However, this approach is essentially a two-dimensional technology and it is unknown whether it can be adapted to the generation of thick, three-dimensional tissues.
PCT US96/09344 by Massachusetts Institute of Technology involves a three-dimensional printing process, a form of solid free form fabrication, which builds three-dimensional objects as a series of layers. This process uses polymer powders in layers bound by polymer binders whose geometry is dictated by computer-assisted design and manufacture. This technique allows defined internal architectures, which could include branching arrays of channels mimicking a vascular supply. However, this technique is limited by the characteristics and chemistry of the particular polymers. Also, it severely limits the types of tissue to be fabricated. For example, these polymer walls do not allow the plasma exchange that is needed in the alveolar capillary wall of the lung.
A further limitation of the prior art methods of tissue engineering is related to mass transport. Cells must be within approximately 100 μm of a capillary blood supply. Tissue engineered constructs without a blood supply develop hypoxia and nutrient deprivation. Without vasculature, cells in constructs larger than 1-2 mm experience significant necrosis. To date, all approaches in tissue engineering have relied on the in-growth of blood vessels into tissue-engineered devices to achieve permanent vascularization. This strategy has worked well for many tissues; however, it falls short for thick, complex tissues such as large vital organs, including liver, kidney, and heart. See Eiselt, et al., Biotechnol. Prog. 14, 134 (1998). Novel methods and devices that enable the production of thick, complex tissue-engineered structures would be highly desirable.